Directly compressible high load acetaminophen formulations

ABSTRACT

Direct compressed solid pharmaceutical dosage forms containing:  
     a) from about 40 to about 95% by weight acetaminophen;  
     b) from about 1 to about 60% by weight of a direct compression vehicle comprising microcrystalline cellulose; and  
     c) from about 0.01 to about 4.0% by weight of a pharmaceutically-acceptable lubricant  
     are disclosed. The acetaminophen and direct compression vehicle are combined under high shear conditions which are sufficient to transform acetaminophen and direct compression vehicle into a homogenous granulate without degradation. In preferred aspects of the invention, the lubricant is also combined with the acetaminophen and direct compression vehicle under high shear conditions. Methods of preparing the directly compressed solid pharmaceutical dosage forms and methods of treatment with the dosage forms are also disclosed. The methods are particularly well suited for preparing directly compressed dosage forms containing high load (i.e., up to 80% or greater) amounts of acetaminophen based on the weight of the total tablet.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to methods of preparing soliddosage forms using direct compression techniques. In particular, thepresent invention relates to methods of directly compressing tabletscontaining relatively high amounts of acetaminophen based on the totaltablet weight.

[0002] In order to prepare a solid dosage form containing one or moreactive ingredients (such as drugs), it is necessary for the materials tobe compressed into the dosage form possess certain physicalcharacteristics which lend themselves to solid dosage form processing.Among other things, the material to be compressed must be free-flowing,must be lubricated, and, importantly, must possess sufficientcohesiveness to insure that the solid dosage form remains intact aftercompression.

[0003] In the case of tablets, the tablet is formed by pressure beingapplied to the material to be tableted on a tablet press. A tablet pressincludes a lower punch which fits into a die from the bottom and a upperpunch having a corresponding shape and dimension which enters the diecavity from the top after the tabletting material fills the die cavity.The tablet is formed by pressure applied on the lower and upper punches.The ability of the material to flow freely into the die is important inorder to insure that there is a uniform filling of the die and acontinuous movement of the material from the source of the material,e.g. a feeder hopper. The lubricity of the material is crucial in thepreparation of the solid dosage forms since the compressed material mustbe readily ejected from the punch faces.

[0004] Since most drugs have none or only some of these properties,methods of tablet formulating have been developed to impart thesedesirable characteristics to the material(s) which is to be compressedinto a solid dosage form. Typically, excipients are added to theformulation which impart good flow and compression characteristics tothe material as a whole which is to be compressed. Such properties aretypically imparted to these excipients via a pre-processing step such aswet granulation, slugging, spray drying, spheronization, orcrystallization. Useful direct compression excipients include processedforms of cellulose, sugars, and dicalcium phosphate dihydrate, amongothers.

[0005] Lubricants are typically added to avoid the material(s) beingtabletted from sticking to the punches. Commonly used lubricants includemagnesium stearate and calcium stearate. Such lubricants are commonlyincluded in the final tabletted product in amounts usually less than 1%by weight.

[0006] In addition, solid dosage forms often contain diluents. Diluentsare frequently added in order to increase the bulk weight of thematerial to be tabletted in order to make the tablet a practical sizefor compression. This is often necessary where the dose of the drug isrelatively small.

[0007] Another commonly used class of excipients in solid dosage formsare binders. Binders are agents which impart cohesive qualities to thepowdered material(s). Commonly used binders include starch, and sugarssuch as sucrose, glucose, dextrose, and lactose.

[0008] Disintegrants are often included in order to ensure that theultimately prepared compressed solid dosage form has an acceptabledisintegration rate in an environment of use (such as thegastrointestinal tract). Typical disintegrants include starchderivatives and salts of carboxymethylcellulose.

[0009] There are three general methods of preparing the materials to beincluded in the solid dosage form prior to compression: (1) drygranulation; (2) wet granulation; and (3) direct compression.

[0010] Dry granulation procedures may be utilized where one of theconstituents, either the drug or the diluent, has sufficient cohesiveproperties to be tabletted. The method includes mixing the ingredientswith a lubricant, if required, slugging the ingredients, dry screening,lubricating and finally compressing the ingredients.

[0011] The wet granulation procedure includes mixing the powders to beincorporated into the dosage form in, e.g., a twin shell blender ordouble-cone blender under shear mixing conditions and thereafter addingsolutions of a binding agent to the mixed powders to obtain agranulation. Thereafter, the damp mass is screened, e.g., in a 6- or8-mesh screen and then dried, e.g., via tray drying or fluid-bed drying.The wet granulating technique is rather time consuming due to itsprocess steps and can also be considered to be relatively expensive. Inaddition, wet granulating has been known to reduce the compressibilityof some pharmaceutical ingredients including microcrystalline cellulose.

[0012] Direct compression, on the other hand, is regarded as arelatively quick process wherein the powdered materials included in thesolid dosage form are compressed directly without modifying theirphysical nature. Usually, the active ingredient, direct compressionvehicle and other ancillary substances, such as a glidant to improve therate of flow of the tablet granulation and lubricant to prevent adhesionof the tablet material to the surface of the dies and punches of thetablet press, are blended in a twin shell blender or similar low shearapparatus before being compressed into tablets. This type of mixing ofthe ingredients was believed to be essential in order to preparepharmaceutically acceptable dosage forms. For example, Remington'sPharmaceutical Sciences, 16th Edition (1980), Arthur Osol, Ed., cautionsartisans that the manner in which a lubricant is added to a formulationmust be carefully controlled. Consequently, lubricants are usually addedto a granulation by gentle mixing. At page 1556, Remington's, warns:“Prolonged blending of a lubricant with a granulation can materiallyaffect the hardness and disintegration time for the resulting tablets.”Further, those of ordinary skill in the art have long believed thatexcessive mixing of a lubricant with the granulate ingredients overcoatsthe granules and reduces the tablet hardness or tablet strength of thecompressed tablets. Thus, for at least these reasons, high shear mixingconditions have not been used to prepare direct compression dosageforms.

[0013] Pharmaceutical manufacturers would often prefer to use directcompression techniques over wet or dry granulation techniques because ofits processing time and cost advantages. Direct compression, however, isusually limited to those situations where the drug or active ingredienthas a requisite crystalline structure and the physical characteristicsrequired for formation of a pharmaceutically acceptable tablet. Often,however, one or more excipients must be combined with the activeingredient before the direct compression method can be used since manyactive ingredients do not have the necessary properties. Since eachexcipient added to formulation necessarily increases the tablet size ofthe final product, artisans were often limited to using directcompression techniques in formulations containing a rather low load ofactive ingredient per compressed tablet. Solid dosage forms containingthe drug to be administered in a relatively high load or dose (e.g., thedrug itself comprises a substantial portion of the total compressedtablet weight), could only be directly compressed if the drug itself hadsufficient physical characteristics (e.g., cohesiveness) for theingredients to be directly compressed.

[0014] For example, acetaminophen, a widely used analgesic, isconsidered to be a high load active ingredient. Most commercialcompressed tablet formulations include anywhere from 70 to 85% by weightacetaminophen per finished tablet. This high load of active ingredientcombined with its rather poor physical characteristics for directcompression have not allowed pharmaceutical manufacturers to use directcompression techniques to prepare the final tablets. Previous attemptsto directly compress acetaminophen with microcrystalline cellulose havefailed to provide an acceptable product. The final products tend to besoft, prone to capping and otherwise not commercially desirable, i.e.,difficult to swallow because of the large size. Consequently, the moretime consuming and expensive wet granulation techniques must be used.

[0015] Thus, another limitation of direct compression as a method oftablet manufacturing is the potential size of the compressed tablet. Ifthe amount of active ingredient is high, a pharmaceutical formulator maychoose to wet granulate the active with other excipients to attain anacceptably sized tablet with the desired amount of acetaminophen.Usually the amount of filler/binder or excipients needed in wetgranulation is less than that required for direct compression since theprocess of wet granulation contributes to some extent toward the desiredphysical properties of a tablet.

[0016] Microcrystalline cellulose, a processed cellulose, has beenutilized extensively in the pharmaceutical industry as a directcompression vehicle for solid dosage forms. Microcrystalline celluloseis commercially available under the tradename EMCOCEL® from EdwardMendell Co., Inc. and as Avicel® from FMC Corp. Compared to otherdirectly compressible excipients, microcrystalline cellulose isgenerally considered to exhibit superior compressibility anddisintegration properties as long as it is not wet granulated prior tocompression.

[0017] Thus, despite the advantages of direct compression such asreduced processing times and costs, wet granulation is widely used inthe industry to prepare solid dosage forms. Currently, many skilled inthe art also prefer wet granulation over direct compression because wetgranulating has a greater probability of overcoming any problemsassociated with the physical characteristics of the various ingredientsin the formulation, thereby providing a material which has the requisiteflow and cohesive characteristics necessary to obtain an acceptablesolid dosage form.

[0018] The popularity of the wet granulation process as compared to thedirect compression process is based on at least three advantages. First,wet granulation provides the material to be compressed with betterwetting properties, particularly in the case of hydrophobic drugsubstances. The addition of a hydrophilic excipient makes the surface ofa hydrophobic drug more hydrophilic, easing disintegration anddissolution. Second, the content uniformity of the solid dosage forms isgenerally improved with the wet granulation method because all of thegranules obtained thereby usually contain approximately the same amountof drug. Thus, segregation of the different ingredients of the materialto be compressed (due to different physical characteristics such asdensity) is avoided. Segregation is a potential problem with the directcompression method. Finally, the particle size and shape of theparticles comprising the granulate to be compressed are optimized viathe wet granulation process. This is due to the fact that when a drysolid is wet granulated, the binder “glues” particles together, so thatthey agglomerate in the granules which are more or less spherical.

[0019] In spite of the advantages afforded by wet granulation methods,many manufacturers would nonetheless welcome the opportunity to directlycompress tablets containing acetaminophen, especially those containinghigh loads of acetaminophen and/or microcrystalline cellulose.

[0020] Thus, there still remains a need in the industry for techniquesand pharmaceutical excipients which would allow artisans to preparedirect compressed dosage forms containing relatively high amounts ofacetaminophen by weight and thereby avoid the time and expense of wetgranulations.

OBJECTS AND SUMMARY OF THE INVENTION

[0021] It is an object of the present invention to provide improvementsin direct compression techniques.

[0022] It is a further object of the present invention to provide a costeffective alternative to wet granulating acetaminophen formulations inorder to prepare solid dosage forms containing a relatively highproportion of the drug when compared to the total weight of the dosageform.

[0023] It is a further object of the present invention to provide directcompressed acetaminophen oral solid dosage forms which disintegraterapidly in vivo and in vitro.

[0024] A further object of the present invention is to provide directcompressed dosage forms which provide controlled release ofacetaminophen without relying on fluidized bed or wet granulatingtechniques.

[0025] Another object of the present invention is to provide soliddosage forms which include acetaminophen and which are preparedaccording to the methods described herein.

[0026] In accordance with the above objects and others which will beobvious to those skilled in the art, the present invention includes adirect compressed solid pharmaceutical dosage form containing:

[0027] a) from about 40 to about 95% by weight acetaminophen;

[0028] b) from about 1 to about 60% by weight of a direct compressionvehicle comprising microcrystalline cellulose; and

[0029] c) from about 0.01 to about 4.0% by weight of apharmaceutically-acceptable lubricant.

[0030] The acetaminophen and direct compression vehicle included in thedirect compressed dosage form are combined under shear mixing conditionswhich are sufficient to transform the acetaminophen and directcompression vehicle into a homogenous granulate without degradation.

[0031] In preferred embodiments of this aspect of the invention, thesolid dosage form comprises from about 60% to about 85% by weightacetaminophen and the acetaminophen is in granular form. The soliddosage forms accordingly can contain from about 10 to about 1000milligrams of acetaminophen. In a particularly preferred embodiment, thedirect compression vehicle includes microcrystalline cellulose which hasbeen coprocessed with from about 0.1 to about 20% by weight silicondioxide so that the microcrystalline cellulose and silicon dioxide arein intimate association with each other and provide enhancedcompressibility properties for the direct compressed dosage forms. Anadditional preferred embodiment includes preparing the direct compressedsolid pharmaceutical dosage form to include from about 0.1 to about 1%by weight of a pharmaceutically acceptable lubricant such as sodiumstearyl fumarate. The lubricant is included as part of the homogeneousmixture containing the acetaminophen and direct compression vehicle andis preferably admixed with these ingredients under the same or similarhigh shear conditions used to form the homogeneous mixture.

[0032] In another embodiment, the direct compressed dosage forms of thepresent invention include from about 0.1 to about 5.0% by weight silicondioxide. The silicon dioxide is preferably combined with the homogeneousmixture containing the acetaminophen and direct compression vehicleduring the same high shear mixing conditions used to transform theingredients into the homogeneous mixture.

[0033] In another embodiment of the invention, the direct compresseddosage forms include a disintegrant which has preferably been high shearmixed with the aforementioned acetaminophen, direct compression vehicleand lubricant.

[0034] One particularly preferred solid dosage form of the presentinvention includes at least about 75% by weight acetaminophen and has anaverage tablet hardness of about 6.5 kP when the homogeneous granulatecontaining the acetaminophen and microcrystalline cellulose is directcompressed at a compression force of about 25 kN.

[0035] The tablets of the present invention also have a relatively rapiddisintegration rate which compares favorably with acetaminophen tabletsprepared using wet granulation techniques. In certain preferredembodiments, the disintegration rate for the tablets of the presentinvention meets the requirements set forth in the USP 23 © 1994 UnitedStates Pharmacopeial Convention, Inc. Furthermore, the dissolution rateof the inventive tablets is also believed to compare favorably, and incertain embodiments, even exceed that of wet granulated APAP products.In certain preferred embodiments, the inventive tablets also meet thedissolution requirements for acetaminophen tablets as set forth in theUSP 23 official monograph. For example, the direct compressed APAPtablets will preferably dissolve in 900 ml of pH 5.8 phosphate buffer in30 minutes. The “dissolution requirements” and “disintegrationrequirements” referred to herein are conducted using the equipment andtests specified in the aforementioned USP 23.

[0036] In another aspect of the present invention, there are providedmethods of preparing direct compressed solid pharmaceutical dosage formscontaining acetaminophen. This aspect of the invention includes firstcombining an effective amount of acetaminophen and a direct compressionvehicle which comprises microcrystalline cellulose under shearconditions which are sufficient to transform the acetaminophen anddirect compression vehicle into a first homogenous granulate withoutdegradation. Next, the homogeneous granulate is combined with apharmaceutically-acceptable lubricant, either by similar high shear orother dry mixing conditions, and thereafter compressing the resultanthomogenous granulate containing the lubricant into solid pharmaceuticaldosage forms.

[0037] Alternative aspects of the inventive methods described hereininclude forming a high shear mixture which includes silicon dioxide,preferably in the form of colloidal silicon dioxide. One particularlypreferred method includes forming a first high shear mixture containingacetaminophen and a direct compression vehicle which includesmicrocrystalline cellulose and silicon dioxide before adding thelubricant under high shear conditions.

[0038] A still further aspect of the inventive method includes preparingdirect compression solid pharmaceutical dosage forms by preparing afirst high shear mixture by combining the acetaminophen, directcompression vehicle and, optional silicon dioxide and/or disintegrant.Next, the first high shear mixture is combined with a lubricant in aseparate shear mixing step to form the final homogenous granulate. Inthis aspect of the invention, however, the second shear mixing step iscarried out under conditions which are milder than those used to carryout the first shear mixing step.

[0039] For purposes of the present invention, the term “high-load” ismeant to indicate that the acetaminophen comprises a substantial portionof the solid oral dosage form on a weight basis. Those of ordinary skillin the art recognize that compressed tablets containing at least about40% by weight of acetaminophen are “high-load” tablets.

[0040] The term “granular” for purposes of the present invention ismeant to connote particles having an average cross-sectional diameter offrom about 50 to about 500 microns. The granular particles are to bedistinguished from powdered particles having a particle size of lessthan about 50 microns and more likely in the range of 10-20 microns.

[0041] The term “environmental fluid” is meant for purposes of theinvention to encompass, e.g., an aqueous solution, or gastrointestinalfluid.

[0042] “Sustained release” is meant for purposes of the invention tomean that the acetaminophen is released from the solid dosage form at acontrolled rate such that therapeutically beneficial blood levels (butbelow toxic levels) of the active ingredient are maintained over anextended period of time, e.g., providing a 12 hour or a 24 hour dosageform.

[0043] “Controlled release” is meant for purposes of the invention tomean that the acetaminophen is released from the solid dosage form at apredetermined rate such that therapeutically beneficial blood levels aremaintained over a period of time.

[0044] By “bioavailable” it is meant for purposes of the invention thatthe acetaminophen is absorbed from the dosage form and becomes availablein the body at the intended site of action.

[0045] By “primary particle size” it is meant for purposes of theinvention that the particles are not agglomerated. Agglomeration iscommon with respect to silicon dioxide particles, resulting in acomparatively average large agglomerated particle size.

[0046] The methods and compositions of the present invention provideseveral advantages to pharmaceutical formulators with regard to directcompression techniques. For example, the methods provide artisans withthe ability to include high-load amounts of acetaminophen in directcompression dosage forms. In the past, high-load oral solid dosage formscontaining acetaminophen could only be prepared using wet granulationtechniques because the amount of additional excipients required toimpart the necessary physical characteristics, such as hardness andsize, rendered the final dosage forms unacceptable for bothmanufacturers and consumers.

[0047] A further advantage of the present invention is that it is nowpossible to increase the tablet hardness of acetaminophen-containingsolid dosage forms by subjecting the formulation to high shear blending.This technique is especially advantageous in situations where one ormore of the formulation ingredients, such as an additional activeingredient, is incapable of undergoing wet granulation.

[0048] For a better understanding of the present invention, togetherwith other and further objects, reference is made to the followingdescription, taken together with the accompanying figures, and the scopeof the invention will be pointed out in the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0049] The following drawings are illustrative of embodiments of theinvention and are not meant to limit the scope of the invention asencompassed by the claims.

[0050]FIG. 1 graphically illustrates the tensile strengths of high loadAPAP tablets prepared in accordance with Examples 3-5, 7, 8, a controlhigh load APAP tablets made in accordance with Example 6 and a secondcontrol prepared using prior art techniques.

[0051]FIG. 2 graphically illustrates a comparison of the tensilestrength of tablets prepared in accordance with Examples 8 and 9-11 andthat obtained for a control high load APAP formulation.

[0052]FIG. 3 is a graphic illustration of the differences in thedisintegration time for a batch of tablets prepared in accordance withthe present invention and commercially available APAP tablets.

DETAILED DESCRIPTION OF THE INVENTION

[0053] In one aspect of the invention, there are provided directcompressed solid pharmaceutical dosage forms comprising:

[0054] a) from about 40 to about 95% by weight acetaminophen;

[0055] b) from about 1 to about 60% by weight of a direct compressionvehicle comprising microcrystalline cellulose; and

[0056] c) from about 0.01 to about 4.0% by weight of apharmaceutically-acceptable lubricant.

[0057] The acetaminophen and direct compression vehicle are combinedunder shear mixing conditions which are sufficient to transform theacetaminophen and direct compression vehicle into a homogenous granulatewithout degradation. The lubricant included in the dosage forms is alsocombined with the homogeneous granulate. In this regard, high shearconditions are preferred although not required.

[0058] ACETAMINOPHEN

[0059] The acetaminophen, hereinafter APAP, used in the directcompressed dosage forms of the present invention is preferably ingranular form and has an average cross-sectional diameter of from about50 to about 500 microns. More preferably, however, the granular APAP hasa cross sectional diameter of from about 250-300 microns. Acetaminophenhaving these physical characteristics is available, for example fromMallinkrodt, St. Louis, Mo. USA. An alternative acetaminophen, alsoavailable from Mallinkrodt is DC-90. It is to be understood that thepresent invention is not limited to these types of granular APAP. Othersources of APAP are also contemplated so long as the APAP has thegranular characteristics set forth above.

[0060] The granular APAP preferably used in the dosage forms of thepresent invention is to be contrasted with powdered forms of the activeingredient. Such powdered forms of APAP have a cross sectional diameterof from about 10-20 microns and are not contemplated for use herein.While applicants are not bound by theory, it is believed that a criticalparticle size is required to successfully withstand the high shearmixing conditions which transform the APAP, in high load amounts, anddirect compression vehicle into a flowable granulate which is capable ofbeing direct compressed into solid dosage forms having sufficienthardness and other physical qualities associated with an acceptabledosage form.

[0061] In a preferred aspect of the invention, the solid dosage formscontain from about 60 to about 85% by weight acetaminophen. Of course,the exact amount of acetaminophen included in the dosage forms of thepresent invention will depend upon the size of tablet and dosage amountcontemplated by the artisan. Currently, APAP tablets are frequentlyformulated to contain from about 160 to about 650 milligrams of thedrug. Tablets containing about 325 and about 500 milligrams are alsocommonly found. Several other APAP formulations are also commerciallyavailable. The tablets of the present invention contain from about 10 toabout 1000 milligrams of APAP, preferably from about 80 to about 750milligrams of APAP and most preferably from about 120 to about 650milligrams of APAP.

[0062] In an alternative aspect of the invention the direct compressedacetaminophen tablets are prepared to contain an additional activeingredient such as those commonly found in APAP products. A non-limitinglist of suitable ingredients which may be combined with the APAPincludes narcotic analgesics such as codeine phosphate, oxycodone andhydromorphone, sinus and/or nasal decongestant ingredients suchpseudoephedrine and antihistamines such as diphenhydramine.

[0063] DIRECT COMPRESSION VEHICLES

[0064] The direct compression vehicles used in the solid dosage forms ofthe present invention represent from about 1 to about 60% by weight ofthe solid dosage form and include microcrystalline cellulose (MCC).Preferably, the solid dosage forms contain from about 2 to about 25 andmost preferably about 5 to about 20% by weight direct compressionvehicle.

[0065] Microcrystalline cellulose is a well-known tablet diluent anddisintegrant. Its chief advantage over other excipients is that it canbe directly compressed into self-binding tablets which disintegraterapidly when placed into water. This widely-used ingredient is preparedby partially depolymerizing cellulose obtained as a pulp from fibrousplant material with dilute mineral acid solutions. Following hydrolysis,the hydrocellulose thereby obtained is purified via filtration and theaqueous slurry is spray dried to form dry, white odorless, tastelesscrystalline powder of porous particles of a broad size distribution.Another method of preparing microcrystalline cellulose is disclosed inU.S. Pat. No. 3,141,875. This reference discloses subjecting celluloseto the hydrolytic action of hydrochloric acid at boiling temperatures sothat amorphous cellulosic material can be removed and aggregates ofcrystalline cellulose are formed. The aggregates are collected byfiltration, washed with water and aqueous ammonia and disintegrated intosmall fragments, often called cellulose crystallites by vigorousmechanical means such as a blender. Microcrystalline cellulose iscommercially available in several grades which range in average particlesize from 20 to 200 microns.

[0066] Microcrystalline cellulose is water-insoluble, but the materialhas the ability to draw fluid into a tablet by capillary action. Thetablets then swell on contact and the microcrystalline cellulose thusacts as a disintegrating agent. The material has sufficientself-lubricating qualities so as to allow a lower level of lubricant ascompared to other excipients.

[0067] Typically, microcrystalline cellulose bulk powder has an apparentdensity of about 0.28 g/cm³ and a tap density of about 0.43 g/cm³ .Handbook of Pharmaceutical Excipients, pages 53-55.

[0068] When utilized in pharmaceutical applications, microcrystallinecellulose is typically used as a tablet binder/diluent in wetgranulation and direct compression formulations in amounts of 5-30% ofthe formulation, or more. However, it is known to use more or lessmicrocrystalline cellulose in pharmaceutical products, depending uponthe requirements of the formulation. In spite of it being known toinclude MCC in direct compression formulations, mere twin shell blendingof APAP and MCC has not provided a mixture which could be directcompressed into an acceptable solid dosage form.

[0069] In one preferred embodiment of the invention, the directcompression vehicle includes a microcrystalline cellulose which has beencoprocessed with from about 0.1 to about 20% silicon dioxide. Thiscoprocessed, direct compression vehicle is an agglomerate ofmicrocrystalline cellulose and silicon dioxide in which themicrocrystalline cellulose and silicon dioxide are in intimateassociation with each other such as that described in commonly-assignedU.S. patent application Ser. No. 08/370,576, the disclosure of which isincorporated by reference herein. Magnifications of these coprocessedparticles indicate that the silicon dioxide is integrated with, orpartially coats, the surfaces of the microcrystalline celluloseparticles.

[0070] The exact relationship of the two ingredients in the excipientafter coprocessing is not presently understood; however, for purposes ofdescription, the coprocessed particles are described herein as includingan agglomerate of microcrystalline cellulose and silicon dioxide inintimate association with each other. By “intimate association”, it ismeant that the silicon dioxide has in some manner been integrated withthe microcrystalline cellulose particles, e.g., via a partial coating ofthe microcrystalline particles, as opposed to a chemical interaction ofthe two ingredients. The term “intimate association” is therefore deemedfor purposes of the present description as being synonymous with“integrated” or “united”. The coprocessed particles are not necessarilyuniform or homogeneous. Rather, under magnification, e.g., scanningelectron microscope at 500×, the silicon dioxide at the preferredpercent inclusion appears to be an “edge-coating”.

[0071] The compressed excipient has a bulk (loose) density ranging fromabout 0.2 g/ml to about 0.6 g/ml, and most preferably from about 0.35g/ml to about 0.55 g/ml. The coprocessed excipient has a tapped densityranging from about 0.25 g/ml to about 0.65 g/ml, and most preferablyfrom about 0.35 g/ml to about 0.55 g/ml. The pH of the particles is mostpreferably about neutral, although granulates having a pH of from about3.0 to about 8.5 are possible. The moisture content of the excipientparticles will broadly range from about 0.5% to about 15%, preferablyfrom about 1.5% to about 7%, and most preferably from about 3.0% toabout 5% by weight.

[0072] The coprocessed excipient can be used alone or in combinationwith “off-the-shelf” MCC in any desired proportion to form the directcompression vehicle included in the novel dosage forms.

[0073] The silicon dioxide coprocessed with microcrystalline in thisaspect of the invention preferably has an average primary particle sizeof from about 1 nm to 1,000 μm. More preferably, however, the silicondioxide has an average primary size of from about 5 nm to 40 μm.

[0074] The silicon dioxide coprocessed with the MCC is preferablyderived from colloidal silicon dioxide and, preferably comprises fromabout 0.5 to 10% by weight of the coprocessed material based on theweight of the microcrystalline cellulose and, more preferably, comprisesfrom about 1.25 to about 5% by weight of the agglomerate based on theweight of the microcrystalline cellulose.

[0075] LUBRICANTS

[0076] The solid dosage forms of the present invention also include asufficient amount of a lubricant. In preferred aspects of the invention,the lubricant selected is sodium stearyl fumarate. Alternatives,however, include magnesium stearate, hydrogenated vegetable oil,LUBRITAB® (Edward Mendell Co., Inc.), stearic acid, PEG, and otherlubricants known to those of ordinary skill in the art.

[0077] In this regard, the lubricant will be present in amounts rangingfrom about 0.01 to about 4.0% by weight of the dosage form. Amounts offrom about 0.1 to about 1.0% by weight are preferred and amounts of fromabout 0.2 to about 0.45% are most preferred.

[0078] In accordance with the present invention, the lubricant iscombined with the homogeneous mixture containing the APAP and directcompression vehicle. It has been surprisingly found that high shearblending of the lubricant with the homogeneous granulate does notadversely affect the tablet hardness of direct compressed dosage forms.While Applicants are not bound by theory, it is proposed that the highshear mixing conditions convey physical properties on thelubricant-containing granulate which are completely contrary to what wasexpected and which are desirable for direct compression of thegranulation.

[0079] ADDITIONAL INGREDIENTS

[0080] A. Silicon Dioxide

[0081] In certain preferred aspects of the invention, the directcompressed pharmaceutical dosage forms include silicon dioxide in anamount which is separate from and in addition to the silicon dioxideincluded with the coprocessed MCC (if used). In this regard, the silicondioxide is preferably colloidal silicon dioxide and is present in anamount of from about 0.1 to about 5% by weight of the dosage form.Preferably, however, the silicon dioxide is present in an amount of fromabout 0.15 to about 0.9% by weight and most preferably in an amount offrom about 0.4 to about 0.75% by weight of the dosage form.

[0082] Silicon dioxide is obtained by insolubilizing dissolved silica insodium silicate solution. When obtained by the addition of sodiumsilicate to a mineral acid, the product is termed silica gel. Whenobtained by the de-stabilization of a solution of sodium silicate insuch a manner as to yield very fine particles, the product is termedprecipitated silica. Silicon dioxide is insoluble in water. Silicondioxide, and in particular colloidal silicon dioxide, is mainly used asa glidant and anti-adherent in tableting processes and encapsulation topromote the flowability of the granulation. Handbook of PharmaceuticalExcipients, ©1986 American Pharmaceutical Association, page 255. This isdue in part to the fact that increasing the amount of silicon dioxide inthe mixture to be tableted causes the mixture to flow too well, causinga phenomena known to those skilled in the tableting art as “flooding”.If the mixture flows too well, a varying tablet weight with unevencontent uniformity can result.

[0083] Those skilled in the art will appreciate that the name and/ormethod of preparation of the silicon dioxide utilized in the presentinvention is not determinative of the usefulness of the product. Rather,it has been surprisingly discovered that high shear mixing of SiO₂ withother formulation ingredients unexpectedly enhances tablet hardness indirect compression dosage forms.

[0084] The present invention encompasses all forms of silicon dioxidehaving an average primary particle size from about 1 nm to about 100 μm,and/or a surface area from about 10 m²/g to about 500 m²/g.

[0085] The silicon dioxide utilized in the invention is of the very fineparticle size variety. In the most preferred embodiments of theinvention, the silicon dioxide utilized is a colloidal silicon dioxide.Colloidal silicon dioxide is a submicron fumed silica prepared by thevapor-phase hydrolysis (e.g., at 1110° C.) of a silicon compound, suchas silicon tetrachloride. The product itself is a submicron, fluffy,light, loose, bluish-white, odorless and tasteless amorphous powderwhich is commercially available from a number of sources, includingCabot Corporation (under the tradename Cab-O-Sil); Degussa, Inc. (underthe tradename Aerosil); E. I. DuPont & Co.; and W. R. Grace & Co.Colloidal silicon dioxide is also known as colloidal silica, fumedsilica, light anhydrous silicic acid, silicic anhydride, and silicondioxide fumed, among others. A variety of commercial grades of colloidalsilicon dioxide are produced by varying the manufacturing process. Thesemodifications do not affect the silica content, specific gravity,refractive index, color or amorphous form. However, these modificationsare known to change the particle size, surface areas, and bulk densitiesof the colloidal silicon dioxide products.

[0086] The surface area of the preferred class of silicon dioxidesutilized in the invention ranges from about 50 m²/gm to about 500 m²/gm.The average primary particle diameter of the preferred class of silicondioxides utilized in the invention ranges from about 5 nm to about 50nm. However, in commercial colloidal silicon dioxide products, theseparticles are agglomerated or aggregated to varying extents. The bulkdensity of the preferred class of silicon dioxides utilized in theinvention ranges from about 20 g/l to about 100 g/l.

[0087] Commercially available colloidal silicon dioxide products have,for example, a BET surface area ranging from about 50±15 m²/gm (AerosilOX50) to about 400±20 (Cab-O-Sil S-17) or 390±40 m²/gm (Cab-O-Sil EH-5).Commercially available particle sizes range from a nominal particlediameter of 7 nm (e.g., Cab-O-Sil S-17 or Cab-O-Sil EH-5) to an averageprimary particle size of 40 nm (Aerosil OX50). The density of theseproducts range from 72.0±8 g/l (Cab-O-Sil S-17) to 36.8 g/l (e.g.,Cab-O-Sil M-5). The pH of the these products at 4% aqueous dispersionranges from pH 3.5-4.5. These commercially available products aredescribed for exemplification purposes of acceptable properties of thepreferred class of silicon dioxides only, and this description is notmeant to limit the scope of the invention in any manner whatsoever.

[0088] In those aspects of the invention where the silicon dioxide is apart of the pharmaceutical dosage form, it is preferred that the silicondioxide be combined with the acetaminophen, direct compression vehicleand lubricant under the same high shear conditions used to create thehomogenous mixture of the solid dosage form ingredients. Alternatively,the silicon dioxide can be high shear blended with the acetaminophen anddirect compression vehicle before the lubricant is combined therewith.

[0089] B. DISINTEGRANT

[0090] A disintegrant may also be included with the other solid dosageform ingredients and subjected to the high shear mixing and, therefore,become part of the homogenous mixture. In one preferred aspect of theinvention, the disintegrant is sodium starch glycolate and will bepresent in amounts ranging from 0.01 to about 4.0% by weight of thedosage form, preferably from about 0.1 to about 2.0% and most preferablyin amounts ranging from about 1.00 to about 1.50% by weight of thedosage form. One particularly useful disintegrant is available under thetrademark Explotab™ available from Edward Mendell Co., Inc. Alternativedisintegrants include, for example, carboxymethylcellulose, cross-linkedpolyvinyl pyrrolidones in amounts similar to that set forth above orstarches, in amounts of from around 4 to about 5%.

[0091] C. ANCILLARY PHARMACEUTICAL INGREDIENTS

[0092] The solid dosage form can also include an inert pharmaceuticalfiller such as a monosaccharide, a disaccharide, a polyhydric alcohol,inorganic phosphates, sulfates or carbonates, and/or mixtures thereof.Examples of suitable inert pharmaceutical fillers include sucrose,dextrose, lactose, xylitol, fructose, sorbitol, calcium phosphate,calcium sulfate, calcium carbonate, mixtures thereof, and the like. Theamount of inert filler, if included, will be an amount which does notdetract from the enhanced tablet hardness achieved by the novel processdescribed herein. In this regard, the amount will be less than 10% byweight of the tablet.

[0093] SHEAR MIXING CONDITIONS

[0094] The present invention includes transforming acetaminophen, adirect compression vehicle and optionally, a pharmaceutically-acceptablelubricant into a homogenous granulate under shear conditions which donot degrade the ingredients. For purposes of the present invention, theshear conditions under which the ingredients are combined can generallybe described as a set of conditions including a combination oftemperature and mechanical forces which permit the formation of thehomogenous granulate but do not break down the materials undergoing theprocessing. For purposes of the present invention, the conditions aredescribed as high shear to distinguish them from the standard blendingachieved by twin shell mixing or tumbling. Suitable apparatus forcarrying out the high shear mixing contemplated herein can include highspeed mixers having an impeller or mixing blade rotating about a centralshaft close to the bottom of the mixing bowl and a chopper or series ofchoppers which consist of fast rotating arms or knives which areinserted into the mixing bowl. This combination of mixing and choppingconfers a mechanical influence or force on the APAP and MCC whichtransforms them into a homogeneous mixture which can be directcompressed even if the APAP constitutes the majority of the granulate ona weight basis. One high shear granulator having an impeller and highshear chopper is available from Baker-Perkins. While such apparatus isusually used to prepare wet granulations, it has been found that whenthe apparatus is operating under dry mixing conditions, it is capable oftransforming the solid dosage form ingredients under shear conditionsinto the homogenous mixture. In this particular apparatus, the operationof the impeller in combination with the chopper creates the shear mixingenvironment. One useful set of parameters with this apparatus forrendering the necessary high shear conditions includes operating theimpeller at about 100 to 300 rpm and the chopper from about 200 to about1,200 rpm. It will be understood, however, that the speeds of theimpeller and chopper can extend beyond the ranges provided with regardto the illustrative device and that optimum operating conditions foralternative shear mixing apparatus will be apparent to those of ordinaryskill without undue experimentation. The simultaneous action of theimpeller and chopper have been found to uniquely transform the soliddosage form ingredients into a mixture which can be directly compressedinto solid pharmaceutical dosage forms having sufficient hardness andsize characteristics suitable for oral delivery of even highload-containing tablets. It is to be understood, however, that theBaker-Perkins apparatus described above is merely illustrative of thetype of apparatus useful in transforming the dosage form ingredients.Those of ordinary skill in the art will realize that other high shearmixing devices can be used, such as a Patterson-Kelly twin shell mixingapparatus equipped with an intensifier bar to facilitate mixing,chopping, shear forces and counter rotating of the ingredients. The Gralhigh shear mixer available from Machines Collette, Inc. Totowa, N.J.operating under dry conditions can also be used.

[0095] In another aspect of the invention, the shear mixing conditionsused to transform the APAP and direct compression vehicle are expressedas a measurement of the vigorousness of the mechanical processing. Onesuch measurement is the relative swept volume, a ratio of the volumethrough which the impeller travels every second to the volume of thebowl. The size of the swept volume is calculated by dividing the area ofeach impeller blade into vertical segments and on the impeller velocity,calculating the volume the impeller blades travel through per second.

[0096] In preferred aspects of the invention, the solid dosage forms ofthe present invention are prepared from a homogenous granulate preparedas a result of a two step, high shear mixing technique. In the firststep, the acetaminophen, direct compression vehicle, and, optionally,disintegrant and/or silicon dioxide, are combined under high shearconditions to form a first high shear mixture which preferably containsthe ingredients in a homogenous distribution. The second step includescombining the first high shear mixture with the lubricant under highshear conditions to form the final homogenous granulate. In preferredaspects of this embodiment, the shear force used to combine thelubricant with the first high shear mixture is less than that used tocombine the ingredients of the first high shear mixture.

[0097] DIRECT COMPRESSION OF APAP GRANULATE

[0098] The present invention also includes methods of preparing solidpharmaceutical dosage forms containing APAP via direct compression. Aspointed out above, direct compression techniques include compressingtablet ingredients directly without modifying the physical nature of anyof the ingredients. In this regard, therefore, the methods include:

[0099] a) combining from about 40 to about 95% by weight acetaminophenand from about 1 to about 60% by weight of a direct compression vehiclecomprising microcrystalline cellose under shear conditions which aresufficient to transform the acetaminophen and direct compression vehicleinto a first homogenous granulate;

[0100] b) combining the first homogenous granulate with from about 0.01to about 4.0% of a pharmaceutically-acceptable lubricant; and

[0101] c) compressing the homogenous granulate containing the lubricantinto a solid pharmaceutical dosage form.

[0102] It is to be understood that the combining steps described aboveare preferably carried out in the high shear mixing apparatus describedabove.

[0103] In preferred embodiments of the present invention, the APAP is ingranular form having a particle size of from about 250 to about 500microns and the direct compression vehicle includes co-processed MCC.

[0104] An alternative method in accordance with the present inventionincludes combining from about 0.1 to about 5% by weight silicon dioxidewith the APAP and direct compression vehicle and subjecting this mixtureto the shear mixing conditions described herein. A disintegrant can alsobe included in this high shear mixture designated herein as a firsthomogeneous granulate. The lubricant can be combined with the firsthomogeneous granulate either by additional high shear mixing or by otherblending techniques such as twin shell blending. It is preferred,however, that the lubricant be combined with the first homogeneousgranulate by additional high shear mixing. In this regard, it ispreferred that the high shear blending used to incorporate the lubricantbe carried out under shear conditions which are less than those used toprepare the first homogeneous granulate. Thus, the lubricant willpreferably be added under shear conditions which include one or morereductions in the mixing parameters i.e. lower mixing or chopping rpm'sand/or shorter mixing times.

[0105] The complete homogeneous high shear mixture, in an amountsufficient to make a uniform batch of tablets, is then subjected totableting in a conventional production scale direct compressiontableting machine at normal compression pressures for that machine,e.g., about 1500-10,000 lbs/sq in. The mixture should not be compressedto such a degree that there is subsequent difficulty in its hydrationwhen exposed to gastric fluid.

[0106] As pointed out above, the solid dosage forms of the presentinvention will contain from 10 to about 1000 milligrams of APAP. Theaverage tablet size for the direct compressed tablets will thereforerange from about 50 mg to 2000 mg. Other formulations prepared inaccordance with the present invention may be suitably shaped for otheruses or locations, such as other body cavities, e.g., periodontalpockets, surgical wounds, vaginally. It is contemplated that for certainuses, e.g., antacid tablets, vaginal tablets and possibly implants, thatthe tablet will be larger.

[0107] One particularly preferred solid dosage form of the presentinvention contains at least about 75% by weight APAP and has an averagetablet hardness of about 6.5 kP when the homogeneous granulate is directcompressed at a compression force of about 25 kN.

[0108] In certain embodiments of the invention, the tablet is coatedwith a sufficient amount of a hydrophobic polymer to render theformulation capable of providing a release of the medicament such that a12 or 24 hour formulation is obtained. The hydrophobic polymer can beselected from materials well known to those of ordinary skill in the artsuch as acrylic acid derivatives. In other embodiments of the presentinvention, the tablet coating may comprise an enteric coating materialin addition to or instead or the hydrophobic polymer coating. Examplesof suitable enteric polymers include cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate,methacrylic acid copolymer, shellac, hydroxypropylmethylcellulosesuccinate, cellulose acetate trimellitate, and mixtures of any of theforegoing. An example of a suitable commercially available entericmaterial is available under the trade name Eudragit™ 100-555.

[0109] In further embodiments, the dosage form may be coated with ahydrophilic coating in addition to or instead of the above-mentionedcoatings. An example of a suitable material which may be used for such ahydrophilic coating is hydroxypropylmethylcellulose (e.g., Opadry®,commercially available from Colorcon, West Point, Pa.).

[0110] The coatings may be applied in any pharmaceutically acceptablemanner known to those skilled in the art. For example, in oneembodiment, the coating is applied via a fluidized bed or in a coatingpan. For example, the coated tablets may be dried, e.g., at about 60-70°C. for about 3-4 hours in a coating pan. The solvent for the hydrophobicpolymer or enteric coating may be organic, aqueous, or a mixture of anorganic and an aqueous solvent. The organic solvents may be, e.g.,isopropyl alcohol, ethanol, and the like, with or without water.

[0111] The coatings which may be optionally applied to the compressedsolid dosage form of the invention may comprise from about 0.5% to about30% by weight of the final solid dosage form.

[0112] In additional embodiments of the present invention, a supportplatform is applied to the tablets manufactured in accordance with thepresent invention. Suitable support platforms are well known to thoseskilled in the art. An example of suitable support platforms is setforth, e.g., in U.S. Pat. No. 4,839,177, hereby incorporated byreference. In that patent, the support platform partially coats thetablet, and consists of a polymeric material insoluble in aqueousliquids. The support platform may, for example, be designed to maintainits impermeability characteristics during the transfer of thetherapeutically active medicament. The support platform may be appliedto the tablets, e.g., via compression coating onto part of the tabletsurface, by spray coating the polymeric materials comprising the supportplatform onto all or part of the tablet surface, or by immersing thetablets in a solution of the polymeric materials.

[0113] The support platform may have a thickness of, e.g., about 2 mm ifapplied by compression, and about 10 μm if applied via spray-coating orimmersion-coating. Generally, in embodiments of the invention wherein ahydrophobic polymer or enteric coating is applied to the tablets, thetablets are coated to a weight gain from about 1% to about 20%, and incertain embodiments preferably from about 5% to about 10%.

[0114] Materials useful in the hydrophobic coatings and supportplatforms of the present invention include derivatives of acrylic acid(such as esters of acrylic acid, methacrylic acid, and copolymersthereof) celluloses and derivatives thereof (such as ethylcellulose),polyvinylalcohols, and the like.

[0115] In certain embodiments of the present invention, the tablet coreincludes an additional dose of a medicament, i.e. APAP, included ineither the hydrophobic or enteric coating, or in an additionalovercoating coated on the outer surface of the tablet core (without thehydrophobic or enteric coating) or as a second coating layer coated onthe surface of the base coating comprising the hydrophobic or entericcoating material. This may be desired when, for example, a loading doseof APAP is needed to provide therapeutically effective blood levels whenthe formulation is first exposed to gastric fluid. The loading dose ofmedicament included in the coating layer may be, e.g., from about 10% toabout 40% of the total amount of medicament included in the formulation.

[0116] The solid formulations of the invention may also include otherlocally active agents, such as flavorants and sweeteners. Generally anyflavoring or food additive such as those described in Chemicals Used inFood Processing, pub 1274 by the National Academy of Sciences, pages63-258 may be used. Generally, the final product may include from about0.1% to about 5% by weight flavorant.

[0117] The tablets of the present invention may also contain effectiveamounts of coloring agents, (e.g., titanium dioxide, F.D. & C. and D. &C. dyes; see the Kirk-Othmer Encyclopedia of Chemical Technology, Vol.5, pp. 857-884, hereby incorporated by reference), stabilizers, binders,odor controlling agents, and preservatives.

[0118] Alternatively, the novel homogenous high shear granulate can beutilized in other applications wherein it is not compressed. Forexample, the granulate can be filled into capsules. The granulate canfurther be molded into shapes other than those typically associated withtablets. For example, the granulate together with acetaminophen can bemolded to “fit” into a particular area in an environment of use (e.g.,an implant). All such uses would be contemplated by those skilled in theart and are deemed to be encompassed within the scope of the appendedclaims.

[0119] A still further embodiment of the present invention is directedto a method of effecting analgesia in mammals. This method includesadministering a dosage form described herein containing an effectiveamount of APAP to a mammal in need of such treatment. In preferredaspects of this embodiment, the dosage forms contain from about 10 toabout 1000 milligrams of APAP and more preferably, from about 120 toabout 750 milligrams of APAP. For purposes of the present invention, theterm “effective amount” shall be understood to include a generallyaccepted amount of APAP for purposes of effecting analgesia for mild tomoderate pain. The method of treatment can also include administeringthe effective amount as a single dose or as multiple doses administeredevery four to six hours as needed.

[0120] A still further aspect of the invention includes homogeneoushigh-shear granulates which are useful as pharmaceutical intermediates.The granulates include:

[0121] a) from about 94 to about 99.99% by weight of a directcompression vehicle comprising microcrystalline cellulose; and

[0122] b) from about 0.01 to about 6.0% by weight of apharmaceutically-acceptable lubricant.

[0123] The direct compression vehicle and pharmaceutically-acceptablelubricant are combined under shear conditions which are sufficient totransform the direct compression vehicle and pharmaceutically-acceptablelubricant into a homogenous granulate without degradation. Theintermediates are thus suitable for admixture with one or more activeingredients such as by additional high shear mixing and thereafterdirect compression into a solid pharmaceutical dosage form.

[0124] The shear conditions under which the intermediate ingredients arecombined are similar to that used for the APAP formulations describedabove. In addition, all other direct compression ingredients, such asdisintegrants, etc., can also be included in the intermediate product aswell.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0125] The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

[0126] The examples set forth the preparation of pharmaceuticalcompositions containing a high load of the active ingredientacetaminophen (APAP) in combination with microcrystalline cellulosebased excipients. Tablets were prepared using each of the compositionsand each of tablet preparations was tested for tensile strength.

EXAMPLES 1-2 Preparation of Coprocessed MCC—SiO₂ Compositions andGranulations Thereof Example 1 MCC—SiO₂ Product—5% w/w SiO₂

[0127] In this example, about 6.2 kilograms of microcrystallinecellulose (MCC), (Mendell Co., Inc. Patterson, N.Y.) in the form of awet cake was combined with 5.2 kilograms of water in a mix tank to forma slurry containing about 15% solids. The pH was adjusted to aboutneutral with about 3 ml of ammonium hydroxide. The slurry was allowed tomix for about 15 minutes before being combined with 5% w/w colloidalsilicon dioxide (CSD), 200 m²/g (CaboSil, PTG grade, available fromCabot Corp., Tuscola, Ill.) After allowing the materials to becomeintimately combined, the slurry was spray dried using a Niro ProductionMinor (Niro, Columbia, Md.), inlet temperature—215° C., outlettemperature—125° C., atomizer wheel speed 22,300 rpm, to provideMCC—SiO₂ having an average particle size of 40-60 microns.

Example 2 MCC—SiO₂ Product—2% w/w SiO₂

[0128] In this example, the process of Example 1 was repeated exceptthat 2% w/w colloidal silicon dioxide was used to form the product.

Examples 3-11

[0129] In these examples, batches of compressed tablets containinggranular acetaminophen (APAP) in high load (80% wt.) were prepared usingthe techniques described herein and compared to a high load (80% byweight) APAP formulation described above wherein all ingredients wereV-blended before being compressed into tablets.

[0130] In each case, the tablets were prepared using a Korsch tabletpress having a punch size of ⅜″ and an aim weight of about 245 mg±5 mg.Each of the foregoing granulations was included in five separatetableting runs using compression forces of 6, 12, 18, 24 and 30 kN,respectively. Ten tablets from each run were weighed, measured fordiameter and tested for thickness and hardness on the Erweka TBH 30tablet hardness tester to determine tensile strength of the finalproduct. The results of the analyses are graphically illustrated inFIGS. 1-2 as a comparison of tensile strength versus compression force.

[0131] The batch formula for the comparative control tablets is setforth below: COMPARATIVE BATCH GRAMS PER INGREDIENT BATCH % BATCHMicrocrystalline cellulose (MCC)  17.80%  44.50 APAP  80.00% 200.00Sodium starch glycolate (SSG)  2.00%  5.00 Mg. Stearate  0.20%  0.50TOTAL 100.00% 250.00

[0132] The MCC, APAP and SSG were added to a two quart V-blender andmixed for 15 minutes. Thereafter, the Mg stearate was added to theblender and mixing was continued for an additional 5 minutes. All mixingof the ingredients was carried out in a room having a relative humidityof about 10%. The mixture was then removed from the blender and tabletedin the same manner as that used to prepare the tablets of the invention.

Example 3

[0133] In this example, compressed tablets containing APAP were preparedaccording to the batch formula set forth below. The microcrystallinecellulose used was the MCC coprocessed with 5.0% SiO₂ as described inExample 1. GRAMS PER INGREDIENT BATCH % BATCH MCC coprocessed w/5% CSD 17.60%  88.00 APAP  80.00% 400.00 Colloidal silicon dioxide (CSD) 0.50%  2.50 Sodium starch glycolate (SSG)  1.50%  7.50 Sodium stearylfumarate (SSF)  0.40%  2.00 TOTAL 100.00% 500.00

[0134] The tablets were prepared according to the following procedure:

[0135] The coprocessed MCC was added to a Baker-Perkins 10L high sheargranulator along with the APAP, CSD and SSG. The CSD added was inaddition to that included in the coprocessed MCC. The ingredients aremixed under dry, high shear conditions for 3 minutes with the impellerset at 200 rpm and the chopper at 1,000 rpm. Thereafter, the sodiumstearyl fumarate, PRUV™, Edward Mendell Co., Inc., was added to the highshear granulator and mixing was continued for an additional 25 secondswith the impeller at 200 rpm and the chopper at 500 rpm. At theconclusion of this mixing step, the dry granulate was removed anddirectly compressed into tablets using the aforementioned Korsch PH-100tablet press and compression forces.

Example 4

[0136] In this example, the procedure of Example 3 was repeated exceptthat the MCC used was “off-the-shelf” MCC (EMCOCEL®, Edward Mendell Co.,Inc.) rather than the silicon dioxide coprocessed material of Example 1.The tablets were prepared using the following batch formula: GRAMS PERINGREDIENT BATCH % BATCH MCC (off-the-shelf)  17.60%  88.00 APAP  80.00%400.00 Colloidal silicon dioxide (CSD)  0.50%  2.50 Sodium starchglycolate (SSG)  1.50%  7.50 Sodium stearyl fumarate (SSF)  0.40%  2.00TOTAL 100.00% 500.00

Example 5

[0137] In this example, the procedure of Example 3 was repeated exceptthat additional CSD was not included in the high shear mixing of theingredients. The batch formula set forth below was used. GRAMS PERINGREDIENT BATCH % BATCH MCC coprocessed w/5% CSD  18.10%  90.50 APAP 80.00% 400.00 Sodium starch glycolate (SSG)  1.50%  7.50 Sodium stearylfumarate (SSF)  0.40%  2.00 TOTAL 100.00% 500.00

Example 6

[0138] In this example an additional control granulation was prepared byV-blending mixing off-the-shelf MCC with the other ingredients in acontrolled environment having a relative humidity of about 40%. Thegranulation also did not include any added silicon dioxide. Theformulation was prepared according to the following batch formula: GRAMSPER INGREDIENT BATCH % BATCH MCC  18.10%  90.50 APAP  80.00% 400.00Sodium starch glycolate (SSG)  1.50%  7.50 Sodium stearyl fumarate (SSF) 0.40%  2.00 TOTAL 100.00% 500.00

Example 7

[0139] In this example, the procedure of Example 3 was followed. In thisbatch, however, the MCC used was the coprocessed product of Example 2which contained 2.0% SiO₂. The batch also did not include a separateamount of added CSD in the high shear mixture. GRAMS PER INGREDIENTBATCH % BATCH MCC coprocessed w/2% CSD  18.10%  90.50 APAP  80.00%400.00 Sodium starch glycolate (SSG)  1.50%  7.55 Sodium stearylfumarate (SSF)  0.40%  2.00 TOTAL 100.00% 500.00

Example 8

[0140] In this example, the directly compressed tablets containing APAPwere prepared using the procedure of Example 3 except that the MCC usedwas the coprocessed microcrystalline cellulose of Example 2. The batchformula set forth below was used. GRAMS PER INGREDIENT BATCH % BATCH MCCcoprocessed w/2% CSD  17.60%  88.00 APAP  80.00% 400.00 Colloidalsilicon dioxide (CSD)  0.50%  2.50 Sodium starch glycolate (SSG)  1.50% 7.50 Sodium stearyl fumarate (SSF)  0.40%  2.00 TOTAL 100.00% 500.00

DISCUSSION

[0141] Referring now to FIG. 1, the results of the tensile strengthtests for the directly-compressed high load tablets are discussed. Eachof the high load-containing APAP tablets made in accordance with thepresent invention had a desirable tablet hardness profile when comparedto that of the V-blended comparative example.

[0142] It can also be seen that mere dry blending of the ingredientsprior to direct compression did not provide acceptable tensile strength.Even in the case of Example 6, where humidity was increased to about40%, the results failed to match that obtained by the high shear mixingof the present invention. Furthermore, the advantages of high shearblending the APAP and MCC-based compression vehicle is especiallyapparent at higher compression forces. The results also point up thefact that those high load tablets prepared with MCC coprocessed withSiO₂, i.e. Examples 3 and 8 as well as those containing a separatelyadded amount of SiO₂, i.e. Example 4, have a particularly desirabletablet hardness profile.

[0143] In general, the results obtained for the inventive compositionswere completely unexpected since those of ordinary skill in the art arewell aware of the problems associated with combining tablet lubricantssuch as sodium stearyl fumarate with the other tablet ingredients underhigh shear conditions. Contrary to what was expected, the directlycompressed high load tablets had higher rather than lower tensilestrength. Further, the overcoating of the granules with the lubricantwhich was expected and which would have significantly reduced the tablethardness was not observed. In addition, it was also unexpected thatgranular forms of APAP would provide the necessary physicalcharacteristics to a formulation to allow formation of direct compressedhigh load tablets having acceptable levels of hardness. Thus, it can beseen that the high shear mixing of MCC-based excipients as describedherein directly addresses a shortcoming of the prior art techniques.

Example 9

[0144] In this example, the tablets were prepared according to thefollowing batch formula: GRAMS PER INGREDIENT BATCH % BATCH MCC(coprocessed w/2% CSD)  17.60%  88.00 APAP  80.00% 400.00 Colloidalsilicon dioxide (CSD)  0.50%  2.50 Sodium starch glycolate (SSG)  1.50% 7.50 Sodium stearyl fumarate (SSF)  0.40%  2.00 TOTAL 100.00% 500.00

[0145] In this example, the initial high shear mixing of the MCC, APAP,CSD, and SSG was carried out in the same manner as described above withregard to Example 4 (i.e., using the high shear blender for 3 minutes at200 rpm for impeller and 1,000 rpm for chopper). However, after thisfirst high shear mixing step, all ingredients were removed andtransferred to a 2 quart V-blender. No further high shear mixing wasundertaken. Instead, the sodium stearyl fumarate was added to themixture and V-blender mixing was carried out for 5 minutes. The tabletswere then made following the procedures described above.

Example 10

[0146] The procedure of Example 11 was repeated except that an equalamount of magnesium stearate was substituted for the sodium stearylfumarate used in Example 11 for the V-blending step prior to the directcompression of the tablets. GRAMS PER INGREDIENT BATCH % BATCH MCC(coprocessed w/2% CSD)  17.60%  88.00 APAP  80.00% 400.0 Colloidalsilicon dioxide (CSD)  0.50%  2.50 Sodium starch glycolate (SSG)  1.50% 7.50 Magnesium stearate  0.40%  2.00 TOTAL 100.00% 500.00

Example 11

[0147] In this example, the two step high shear blending procedure ofExample 4 was repeated except that magnesium stearate was substitutedfor the originally described sodium stearyl fumarate. As was the case inExample 4, high shear mixing was used for both performing both theinitial and final blends. GRAMS PER INGREDIENT BATCH % BATCH MCC(off-the-shelf)  17.60%  88.00 APAP  80.00% 400.00 CSD  0.50%  2.50 SSG 1.50%  7.50 Magnesium stearate  0.40%  2.00 TOTAL 100.00% 500.00

DISCUSSION

[0148]FIG. 2 graphically provides the results for the comparison of thetwo step high shear mixed, direct compressed tablets of Example 8 withthe high shear, then low shear mixed formulations of Examples 9 and 10and the V-blended control formulation. The graph also provides theresults for the two step high shear formulation of Example 11, whichincluded magnesium stearate instead of sodium stearyl fumarate in thesecond high shear mixing step.

[0149] In each case, it can be seen that improvements in tablet hardnesscan be realized even if the lubricant is combined under low shearconditions. In all cases, the tablets prepared from granulations whichwere prepared using at least one high shear mixing step out-performedthe completely V-blended control.

Example 12

[0150] In this example, the average disintegration time for tabletsprepared in accordance with Example 8 was determined and compared tothat of commercially available APAP tablets sold under the Tylenol®brand. The test was carried out according to the U.S.P. guidelines usinga Van-Kel disintegration apparatus. In particular, six tablets preparedaccording to the procedure of Example 8 as well as six Tylenol tabletswere individually evaluated in the apparatus to determine disintegrationtime in deionized water at 37° C. without using the basket disk of theapparatus. The average disintegration time for the six tablets in eachgroup was then calculated and illustrated as a graph which is set forthas FIG. 3.

[0151] As can be seen from the graph, the tablets prepared in accordancewith the present invention had an average disintegration time of lessthan half of that required for the commercially sold formulation. Thisrapid disintegration feature illustrates an additional advantage of theformulations of the present invention.

[0152] While there have been described what are presently believed to bethe preferred embodiments of the invention, those skilled in the artwill realize that changes and modifications may be made thereto withoutdeparting from the spirit of the invention. It is intended to claim allsuch changes and modifications that fall within the true scope of theinvention.

What is claimed is:
 1. A direct compressed solid pharmaceutical dosageform, comprising: a) from about 40 to about 95% by weight acetaminophen;b) from about 1 to about 60% by weight of a direct compression vehiclecomprising microcrystalline cellulose; and c) from about 0.01 to about4.0% by weight of a pharmaceutically-acceptable lubricant; saidacetaminophen and said direct compression vehicle being combined undershear conditions sufficient to transform said acetaminophen and saiddirect compression vehicle into a homogenous granulate withoutdegradation, and which has been directly compressed into a solidpharmaceutical dosage form.
 2. The solid dosage form of claim 1 ,wherein said pharmaceutical dosage form comprises from about 60% toabout 85% by weight acetaminophen.
 3. The solid dosage form of claim 1 ,wherein said acetaminophen is in granular form.
 4. The solid dosage formof claim 1 , wherein said microcrystalline cellulose has beencoprocessed with from about 0.1 to about 20% by weight silicon dioxide,whereby said microcrystalline cellulose and said silicon dioxide are inintimate association with each other.
 5. The solid dosage form of claim4 , wherein said silicon dioxide has an average primary particle size offrom 1 nm to about 100 μm.
 6. The solid dosage form of claim 5 , whereinsaid silicon dioxide has an average primary particle size of from about5 nm to about 40 μm.
 7. The solid dosage form of claim 6 , wherein saidsilicon dioxide is derived from colloidal silicon dioxide.
 8. The soliddosage form of claim 7 , wherein said silicon dioxide is present in anamount of from about 0.5 to about 10% by weight, based on the weight ofsaid microcrystalline cellulose.
 9. The solid dosage form of claim 8 ,wherein said silicon dioxide is present in an amount of from about 1.25to about 5% by weight, based on the weight of said microcrystallinecellulose.
 10. The solid dosage form of claim 1 , wherein said lubricantis sodium stearyl fumarate.
 11. The solid dosage form of claim 1 ,wherein said lubricant is present in an amount of from about 0.1 toabout 1.0% by weight.
 12. The solid dosage form of claim 11 , whereinsaid lubricant is present in an amount of from about 0.2 to about 0.45%by weight.
 13. The solid dosage form of claim 1 , wherein saidhomogeneous granulate further comprises silicon dioxide.
 14. The soliddosage form of claim 13 , wherein said silicon dioxide has been combinedwith said acetaminophen and said direct compression vehicle under saidhigh shear conditions.
 15. The solid dosage form of claim 13 , whereinsaid silicon dioxide is colloidal silicon dioxide.
 16. The solid dosageform of claim 13 , wherein said amount of silicon dioxide is from about0.1 to about 5% by weight of said dosage form.
 17. The solid dosage formof claim 16 , wherein said amount of silicon dioxide is from about 0.15to about 0.9% by weight of said pharmaceutical dosage form.
 18. Thesolid dosage form of claim 17 , wherein said amount of silicon dioxideis from about 0.4 to about 0.75% by weight of said pharmaceutical dosageform.
 19. The solid dosage form of claim 1 , further comprising adisintegrant.
 20. The solid dosage form of claim 19 , wherein saiddisintegrant has been combined with said acetaminophen and said directcompression vehicle under said high shear conditions.
 21. The soliddosage form of claim 19 , wherein said disintegrant is sodium starchglycolate.
 22. The solid dosage form of claim 19 , wherein said directcompression vehicle is present in an amount of from about 2 to about 25%by weight of said solid dosage form.
 23. The solid dosage form of claim22 , wherein said direct compression vehicle is present in an amount offrom about 5 to about 20% by weight of said solid dosage form.
 24. Thesolid dosage form of claim 15 , wherein said silicon dioxide is combinedwith said acetaminophen and said direct compression vehicle to form afirst high shear mixture and thereafter combining said first high shearmixture with said lubricant under said shear conditions to form saidhomogenous granulate.
 25. The solid dosage form of claim 1 , whereinsaid acetaminophen comprises at least about 75% by weight of said soliddosage form and said solid dosage form has an average tablet hardness ofabout 6.5 kP when said homogeneous granulate is direct compressed at acompression force of about 25 kN.
 26. The solid dosage form of claim 1 ,wherein said pharmaceutical dosage form comprises from about 10 to about1000 milligrams of acetaminophen.
 27. The solid dosage form of claim 26, wherein said pharmaceutical dosage form comprises from about 80 toabout 750 milligrams acetaminophen.
 28. The solid dosage form of claim27 , wherein said pharmaceutical dosage form comprises from about 120 toabout 600 milligrams of acetaminophen.
 29. A method of preparing adirect compressed solid pharmaceutical dosage form, comprising: a)combining from about 40 to about 95% by weight acetaminophen and fromabout 1 to about 60% by weight of a direct compression vehiclecomprising microcrystalline cellose under shear conditions sufficient totransform said acetaminophen and said direct compression vehicle into afirst homogenous granulate; b) combining said first homogenous granulatewith from about 0.01 to about 4.0% of a pharmaceutically-acceptablelubricant; and c) compressing said homogenous granulate containing saidlubricant into a solid pharmaceutical dosage form.
 30. The method ofclaim 29 , wherein said pharmaceutical dosage form comprises from about60% to about 85% by weight acetaminophen.
 31. The method of claim 29 ,wherein said acetaminophen is in granular form.
 32. The method of claim29 , wherein said microcrystalline cellulose has been coprocessed withfrom about 0.1 to about 20% by weight silicon dioxide, whereby saidmicrocrystalline cellulose and said silicon dioxide are in intimateassociation with each other.
 33. The method of claim 32 , wherein saidsilicon dioxide is colloidal silicon dioxide and has an average primaryparticle size of from 1 nm to about 100 μm.
 34. The method of claim 32 ,wherein said silicon dioxide is present in an amount of from about 0.5to about 10% by weight, based on the weight of said microcrystallinecellulose.
 35. The method of claim 29 , wherein said lubricant is sodiumstearyl fumarate.
 36. The method of claim 29 , wherein said lubricant ispresent in an amount of from about 0.01 to about 4.0% by weight.
 37. Themethod of claim 1 , wherein said first homogeneous granulate furthercomprises silicon dioxide.
 38. The method of claim 37 , wherein saidsilicon dioxide has been combined with said acetaminophen and saiddirect compression vehicle under said high shear conditions.
 39. Themethod of claim 37 , wherein said silicon dioxide is colloidal silicondioxide.
 40. The method of claim 37 , wherein said amount of silicondioxide is from about 0.1 to about 5% by weight of said dosage form. 41.The method of claim 29 , further comprising combining a disintegrantwith said acetaminophen and said direct compression vehicle under saidhigh shear conditions.
 42. The method of claim 41 , wherein saiddisintegrant is sodium starch glycolate.
 43. The method of claim 29 ,wherein said direct compression vehicle is present in an amount of fromabout 2 to about 25% by weight of said solid dosage form.
 44. The methodof claim 37 , wherein said silicon dioxide is combined with saidacetaminophen and said direct compression vehicle to form a first highshear mixture prior to said combining of said lubricant.
 45. The methodof claim 29 , wherein said lubricant is combined with said firsthomogeneous granulate under high shear mixing conditions.
 46. The methodof claim 45 , wherein said high shear mixing conditions used to combinesaid lubricant are less than said shear conditions used to form saidfirst homogeneous granulate.
 47. A method of effecting analgesia inmammals, comprising administering to a mammal in need of such analgesiaa direct compressed dosage form containing: a) from about 40 to about95% by weight acetaminophen; b) from about 1 to about 60% by weight of adirect compression vehicle comprising microcrystalline cellulose; and c)from about 0.01 to about 4.0% by weight of a pharmaceutically-acceptablelubricant; said acetaminophen and said direct compression vehicle beingcombined under shear conditions sufficient to transform saidacetaminophen and said direct compression vehicle into a homogenousgranulate without degradation.
 48. The method of claim 47 , wherein saidcompressed dosage form comprises from about 10 to about 1000 milligramsof acetaminophen.
 49. The method of claim 48 , wherein said compresseddosage form comprises from about 120 to about 750 milligrams ofacetaminophen.